NL8001289A - PYRIMIDINE DERIVATIVES, PROCESS FOR PREPARING THEREOF AND PHARMACEUTICAL PREPARATIONS PREPARED THEREFROM. - Google Patents

Description

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Pyrimidine derivatives, process for the preparation thereof and pharmaceutical preparations prepared therefrom.

The invention relates to new hydroxy derivatives of 2-isopropylaminopyrimidine of the formula 1 wherein A 1, A <1 and Ag represent a hydrogen atom or hydroxy group, with the proviso that at least one of the symbols A 1, A <and Ag represents no hydrogen atom.

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The compounds of the invention have pharmacological properties and can be used for nerve repair and treatment of muscular dystrophy.

For example, the compounds of the invention can be prepared by reacting 2-thiomethylpyrimidine and isopropylamine in a non-polar solvent at 100 DEG-120 DEG C. under pressure (see the reaction scheme).

Example I

k-hydroxy-2-isonronylaminopyrimidine

Methylthiouracil, prepared from methyl iodide and thiouracil in the presence of sodium methanolate, is placed in a 1 L pressure reactor in an amount of 20 g (0.1 µ mol) together with 200 ml of dry toluene and 200 ml of isopropylamine.

After 2 hours at 110-120 ° C under pressure, the reaction mixture is evaporated to dryness. The residue is treated with a mixture of equal parts by volume of acetone and diethyl ether, filtered, washed with water and crystallized in isopropyl acetate. Thus, 17 g (yield 8U%) of a white crystalline product with a melting point of 100 ° C are obtained. The values found in the elemental analysis correspond well with the values calculated for C-H ,, N_0 25 να T μ 3.

The hydrochloride of the compound prepared is also a white crystalline product, which has a melting point of 800 1 2 89 2 233-23 * C (Tottoli).

U.V. spectrum: in water (hydrochloride) in methanol (base) λ: 266 nm. e] * * 210 λ: 293 nm e! * = 510 max 1 cm max 1 cm 5 λ: 217 nm e! * * 7 ^ 0 λ: 222 nm e] * * 730 max 1 cm max 1 cm λ-: 290 nm max

The free base (molecular weight 153.18) is soluble in chloroform and insoluble in water.

Example II

1Q 5-hydroxy-2-isopropylaminopyrimidine

The title compound is prepared from 5-hydroxy-2-thiomethylpyrimidine according to Example I at a temperature of 105 ° C. Yield: 83%. Melting point: 161 ° C (Tottoli). U.V. spectrum (measured on a solution in a mixture of 60 parts by volume of water and 1 + 0 parts by volume of methanol): λ: 31 + 1 nm e] * = 205 max 1 cm λ: 21 + 1 nm e '0 = 1210 max 1 cm

Example III

k, 6-dihydroxy-2-isopronylaminopyrimidine The title compound is prepared from i + jö-dihydro-2-thiomethylpyrimidine according to Example I at a temperature of 110 ° C, Yield: 67% Melting point of the hydrochloride of the formula C ^ H ^ N ^ HCl: 215-220 ° C (decompn., Tottoli). The white crystalline hydrochloride is insoluble in water at room temperature.

Toxicity

The acute toxicity (mg / kg) of the compounds 2Q according to Examples I-III was determined in mice. The compounds were administered both orally and intraperitoneally. The values obtained are shown in Table A below.

80 0 1 2 89 *>, -i 3

Table A

connection connection connection according to according to according to

example I example II example III

5 200 (i.p.) 2k0 (i.p.) 260 (i.p.) 205 (p.o.) 355 (p.o.) 2Ö5 (p.o.)

Pharmacological action

The nervous repair capacity of the compounds of Examples I-III was examined as follows.

In the adult male rat sciatic nerve (Wistar), a lesion was made by treating the nerve thermosone at -20 ° C for 20 min. After this, each test compound was administered intraperitoneally at a dose of 10 mg / kg to 5 groups of 8 test animals during resp. 7, 11, 1k, 15, 17 and 21 days. For comparison, a mixture of vitamins B1 (500 mg / kg), Bö (500 mg / kg) and B12 (5 mg / kg) was included, which is known to be the most effective nerve repair agent. A control group was not administered anything. The rats were then sacrificed and the sciatic nerve removed and placed over 70 parallel thin platinum wires 1 mm apart. An electrical signal was communicated to the wires above the lesion point. The distance of the wire from the lesion point at which the signal was received was determined. This distance is a measure of nerve recovery: as the length of the recovering nerve increases, the signal is received at a greater distance. The length of the repairing nerve was measured in mm. The results are summarized in Table B below. Where no figures are given, this means that the regenerated length exceeded that of the sample.

800 1 2 89 k

Table B

number of days of administration 7 11 1¾ 17 21 blank 5.1 10.2 12.3 17.8 22, k * 5 compound according to example I 6.6 1 ^, 1 26.3 compound according to example II 6.8 11 +, ¾ 26.1 compound according to example III 6.7 15.6 26.7 B1, B6, B12 8.8 13, ¾ 15.8 20, ¾ 23.7 x Average length in mm.

Posology

The compounds of the invention can be administered orally, for example, as tablets or gelatin capsules containing 5 mg of the active compound. For injections, a pharmaceutically acceptable salt such as the hydrochloride is dissolved in water. Vials are filled with the solution in an amount of at least 1 mg of active ingredient. Oral preparations can be administered in doses from 20 mg to 1 g per day and injectable preparations in doses from 1 mg to 50 mg per day.

For example, a tablet may be composed as follows:

Tablet 25 active compound 5 mg lactose 70 mg talc 20 mg magnesium stearate 5 mg 100 mg 800 1 2 89

Claims (4)

A pyrimidine derivative characterized by the formula 1 wherein A 1, and Ag each represent a hydrogen atom or hydroxy group with the proviso that at least one of the 5 symbols A 1, and Ag does not represent a hydrogen atom, as well as pharmaceutically acceptable salts thereof. 2. A process for the preparation of a pyrimidine derivative, characterized in that a compound of the formula 1 in which A ^, A, is prepared. and Ag each represent a hydrogen atom or hydroxy-10 group, with the proviso that at least one of the symbols A, A, and Ag does not represent a hydrogen atom, by reacting 2-thiomethylpyrimidine and isopropylamine in a non-polar solvent at a temperature of 100 -120 ° C under pressure, optionally followed by conversion of the compound 15 formed into a pharmaceutically acceptable salt. Pharmaceutical preparation, characterized in that the preparation as active ingredient contains a compound of the formula I wherein A ^, A ^ and Ag each represent a hydrogen atom or hydroxy group, with the proviso that at least one of the symbols A ^, and Ag does not represent a hydrogen atom, or a pharmaceutically acceptable salt thereof alternatively as prepared by the method of claim 2. 4. Compounds, method and pharmaceutical preparations as described in the description and examples. 800 1 2 89 AN ^ _> = rlN / CHj α * I At Reaction equation AWn yCHj Ay = \ / CHj As - (\) -S-CH, * HtN-'CH - ^ Ai -— <Λ /) - NH -C ^ V_ H> CHj / —N CHS 'A' 800 1 2 89 SOCIETE DTETUDES DE PRODUHS CHIMIQUES, Societe Anonyme under French law, Paris, France